BMS-777607 is a selective and potent small-molecule met kinase inhibitor for c-Met, Axl, Ron and Tyro3 with IC50s of 3.9 nM, 1.1 nM, 1.8 nM and 4.3 nM, respectively. BMS 777607 inhibits hepatocyte growth factor (HGF)-triggered c-Met autophosphorylation with IC50 of < 1 nM in PC-3 and DU145 prostate cancer cells. BMS-777607 suppressed HGF-stimulated cell migration and invasion in a dose-dependent fashion (IC50 < 0.1 μmol/L). Treatment with BMS 777607 (appr 1 μM) for 24 hours potently inhibits the KHT cell scatter, motility and invasion at doses in the nanomolar range which consists with MET gene knockdown, and modestly affects cell proliferation and colony formation.
Administration of BMS 777607 (25 mg/kg/day) decreases the number of KHT lung tumor nodules (28.3%), improves the morphological hemorrhage, and significantly impairs the metastatic phenotype in the 6-8 week-old female C3H/HeJ mice injected with rodent fibrosarcoma KHT cells without apparent systemic toxicity compared to the control treatment.
 |
Source | Mol Oncol (2014). Figure 2. BMS-777607 |
| Method | Western blot | |
| Cell Lines | breast cancer cells | |
| Concentrations | 5 μM | |
| Incubation Time | 72 h | |
| Results | Thus, results demonstrate that expression of p21/WAF1 and survivin is up-regulated in BMS-777607 induced polyploid/senescent cells regardless the status of p53. |
 |
Source | Mol Oncol (2014). Figure 1. BMS-777607 |
| Method | senescence detection assay | |
| Cell Lines | BMS-777607. T-47D and ZR-75-1 cells | |
| Concentrations | 5 μM | |
| Incubation Time | 72 h | |
| Results | The percentages of SABG-positive cells were associated with increased doses of BMS-777607. |
| Cell Experiment | |
|---|---|
| Cell lines | PC-3 cell line |
| Preparation method | Cell proliferation and cell death Cells were seeded in a 96-well plate at a density of 5 × 103 cells per well and exposed to serial dilutions of BMS-777607 for 1 hour. HGF (25 ng/mL) was then added and the cells were incubated (drug plus HGF) for a period of 96 hours. At the end of the treatment period, the tumor cells were exposed to WST-8 (MTT assay reagent) in a Cell Counting kit (Donjindo Molecular Technologies) according to the manufacturer's instruction, and absorbance was determined at 450 nm colorimetrically. Cell proliferation (%) was calculated as the ratio of absorbance from treated sample to the nontreated control. Cell death was examined by trypan blue exclusion, and positively stained (dead) cells were scored using a hemocytometer. |
| Concentrations | 0, 0.1, 0.3, 1, 3, 10 μM |
| Incubation time | 96 h |
| Animal Experiment | |
|---|---|
| Animal models | C3H/HeJ mice with KHT lung tumor model |
| Formulation | DMSO |
| Dosages | 25mg/kg daily |
| Administration | oral gavage |
| Molecular Weight | 512.89 |
| Formula | C25H19ClF2N4O4 |
| CAS Number | 1196681-44-3 |
| Solubility (25°C) | DMSO 40 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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